Despite advances in early detection and increased understanding of the molecular basis of breast cancer biology, approximately 30% of all patients with early-stage breast cancer have recurrent disease. In most breast cancer cases, the relapsed tumors are metastatic and refractory to subsequent treatment of the initial drug regimen. Recent evidence has implicated that acquired resistance can arise from chemotherapy-induced mutations and increase tumor cell capacity to either repair or tolerate DNA damage. Therefore, the depletion of crucial gene products involved in these pathways (e.g. Rev1 and Rev3) by RNAi therapeutics may restore the tumors chemosensitivity to treatment. Although considerable efforts have been made to explore various delivery systems for chemotherapeutics and small interfering RNA (siRNA), there remains a pressing need towards engineering nanocarriers that are clinically relevant, biocompatible, efficient, and can be tailored to specific disease targets. The objective of this proposal is to develop a versatile nanocarrier platform capable of co- delivering siRNA (anti-Rev1 and Rev3) and cisplatin for enhanced treatment of breast cancer through synergistic effects. This proposed research is based on the hypothesis that suppression of the mutagenic translesion DNA polymerases could prevent chemoresistance from arising during treatment and restore breast tumors' chemosensitivity to treatment. Thus, nanocarriers capable of simultaneously delivering gene specific siRNA (anti-Rev1 and Rev3) and cisplatin present a promising nanotherapeutic approach for breast cancer treatment. The major objective of the proposed project is to develop an innovative two-in-one nanomedicinal approach to codeliver therapeutic siRNA (e.g., anti-Rev1 and Rev3 siRNA) and platinum-based chemotherapeutics (e.g., cisplatin) within a single polymer-lipid hybrid nanoparticle (NP) for breast cancer treatment. A library of hybrid NPs with tunable physicochemical properties will be developed using cationic lipid compounds and poly (lactide-co-glycolide)-b-poly (ethylene glycol) (PLGA-PEG). The building blocks of the PLGA-PEG copolymer (PLGA and PEG) are widely used in FDA-approved implantable and injectable drug delivery systems and have a long history as safe, biodegradable materials, which are capable of encapsulating small- and macro-molecular payloads with a wide range of physiochemical properties, and can be designed for controlled release through a combination of polymer degradation and drug diffusion. This research presents a promising therapeutic strategy through the synergy among different therapeutics with unique mechanisms. If successful, could significantly improve therapeutic outcomes for breast cancer patients that are underserved by existing therapies and so enhance their quality of life.